HJAR Jan/Feb 2021

24 JAN / FEB 2021  I  HEALTHCARE JOURNAL OF ARKANSAS COVID-19 VACCINE 2.0 Vaccine development utilizing various platforms is one of the strategies that has been proposed to address the coronavi- rus disease 2019 (COVID-19) pandemic. Adjuvants are critical components of both subunit and certain inactivated vaccines because they induce specific immune re- sponses that are more robust and long- lasting. A review of the history of corona- virus vaccine development demonstrates that only a few adjuvants, including alu- minum salts, emulsions, and TLR agonists, have been formulated for the severe acute respiratory syndrome-associated corona- virus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS- CoV), and currently the SARS-CoV-2 vac- cines in experimental and pre-clinical studies. However, there is still a lack of evi- dence regarding the effects of the adjuvants tested in coronavirus vaccines. This paper presents an overview of adjuvants that have been formulated in reported corona- virus vaccine studies, which should assist with the design and selection of adjuvants with optimal efficacy and safety profiles for COVID-19 vaccines. Introduction Coronaviruses (CoVs) are single-strand- ed RNA viruses characterized by club-like spikes that can potentially cause severe respiratory disease in humans (1, 2). The outbreak of severe acute respiratory syn- drome (SARS) caused by the SARS-CoV resulted in more than 8000 confirmed in- fections, with an overall case fatality rate of 10% in 2002 (3). The Middle East respira- tory syndrome (MERS)-CoV continues to cause deaths with increasing geographical distribution and a 34.4% case fatality rate, according to the World Health Organiza- tion (WHO) (4). Most recently, the corona- virus disease 2019 (COVID-19) caused by SARS-CoV-2 has spread globally, with over 33 million confirmed cases as of October 2020 (5). Considering the challenges to global health systems and the far-reaching consequences on the world economy, there is an urgent need to develop effective and ated with protection against SARS-CoV-2 (15, 16, 24). However, alum lacks the capa- bility to promote the activation of CD4+ and CD8+ T cell responses, which has been demonstrated to coordinate with the an- tibody responses to provide protective immunity against the SARS-CoV-2 (33). Other adjuvants, e.g., emulsion adjuvants and TLR agonists, which have been shown to induce both humoral and cellular im- mune responses could be more favorable. However, no phase III clinical trial results of COVID-19 vaccines are published so far, thus, there is no direct evidence to indicate which type of immune response induced by vaccine plays a more critical protec- tive role in SARS-CoV-2 infection. Knowing these uncertainties, an overview of previ- ous CoV vaccine studies using different adjuvants would be indispensable for the design and development of a COVID-19 vaccine. The SARS-CoV-2 is a novel strain of the coronavirus, and very little is known about its epidemiology and pathogenesis. Therefore, extreme cautions should be taken when considering vaccine formula- tions that can achieve the desired efficacy and safety profiles. The selection of adju- vants should consider the magnitude, af- finity, isotype, and durability of antibodies that are critical for coronavirus vaccine developments (34). It should be noted that low antibody production may lead to antibody-dependent enhancement (ADE) manifested by severe liver damage and enhanced infection (35), while high affinity neutralizing antibodies could help to avoid ADE. Additionally, the proper application of adjuvants also depends on the choice of antigens. The full-length S protein is more likely to trigger ADE due to mild antibody production (36). In comparison, the N pro- tein is generally highly conserved, and it is associated with the ability to induce cy- totoxic T lymphocytes (CTL). However, N protein could potentiate pro-inflammatory cytokine production and lead to severe lung pathology (37). In addition, previous study on respiratory syncytial virus (RSV) safe vaccines that can be quickly deployed on a global scale (2, 6). Vaccine candidates are currently under development using different platforms, such as inactivated vaccines, recombinant protein vaccines, live-attenuated vaccines, viral vector (adenovirus) vaccines, DNA vaccines, and mRNA vaccines (2, 6, 7). Ade- novirus-vector could induce potent immu- nological responses due to the presence of viral proteins and stimulation of innate im- munity sensors, e.g., toll-like receptors (8). Nucleic-acid vaccines, e.g., DNAand mRNA vaccines, encode the virus’s spike protein, intrinsically could engage innate immunity that instructs induction of immune protec- tion (9). However, these platforms haven’t been used in licensed human vaccines be- fore. In other platforms, subunit or inacti- vated antigens were used, but these anti- gens lack the immunological profiles that mediate the enhanced adaptive immunity. Thus, in these CoV vaccines, they require the addition of adjuvants for directing the types and magnitude of immune responses (10). In previously reported exploratory and pre-clinical CoV vaccine studies, adjuvants such as aluminum salts, emulsions, and toll-like receptor (TLR) agonists, have been used in vaccine formulations for studies with various animal models (Table 1). The adjuvants AS03, MF59, and CpG 1018 have already been used in licensed vaccines (28) and have been committed by GlaxoSmith- Kline, Seqirus, and Dynavax to be available for COVID-19 vaccine development (29). When combined with subunit and specific inactivated antigens (30, 31), adjuvants with various characteristics elicit distinc- tive immunological profiles with regard to the direction, duration, and strength of immune responses. Thus far, there are at least 40 candidate vaccines in clinical tri- als and 149 vaccines in preclinical evalua- tion, of which 67 subunit and 15 inactivated COVID-19 vaccines have being developed (32). Among these adjuvants, alum have been formulated with S protein or RBD to induce neutralizing antibody production (17, 18), which has suggested to be associ-